Amidine intramolecular arylation

To date, most of the reported copper-mediated iV-arylations applied toward benzimidazoles use a polar organic solvent (e.g., DMA, 1,4-dioxane, DMSO, or NMP.) Peng and co-workers have recently reported a modified intramolecular arylation of amidines to provide C2-alkyl and aryl benzimidazoles in moderate to high yield. Remarkably, these arylations, which use CuaO (5 mol%), dimethylethylenediamine (DMEDA, 10%), and K2CO3, are conducted in water, lending potential environmental and economic advantage to this method. 

Using a somewhat different C-H functionalization approach to benzimidazoles, Punniyamurthy and co-workers have explored the conversion of A -benzyl bisarylhydrazones to 2-aryl-A -benzyl-benzimidazoles. This conversion is optimally achieved using stoichiometric Cu(OTf)2 in toluene at 110 °C. (This transformation was also reported using catalytic Cu(OTf)2 (20 mol%) under an oxygen atmosphere, albeit in lower yield). This reaction likely proceeds via a copper-amidine intermediate analogous to the intermediate accessed by Brasche and Buchwald in their direct intramolecular arylation of iV-aryl amidines. 

Intramolecular construction of the key C—N bond has, as in the synthesis of indoles, proven to be a popular strategy in synthesizing benzimidazoles. Brain et al. adopted this approach and developed a synthesis of benzimidazoles via an intramolecular arylation of amidine substrates (Scheme 24.10, disconnection D-1) [54,55]. Thus, amidines such as 26 could be converted into the desired heterocycles under the action of a Pd2(dba)3/triphenylphosphine catalyst using low catalyst loadings and microwave irradiation (Scheme 24.11). 

In 2002, the Brain group reported that Pd-catalyzed intramolecular aryl amination of (2-bromophenyl)amidines 46 worked in refluxing toluene to afford substituted benzimidazoles 47 [43]. Subsequently, they found that the reaction could proceed better by using the catalytic system of Pd2(dba)3/PPh3 under the promotion of microwave (Scheme 15) [44],... 

Chang et al. reported a mild tandem intramolecular hydroamination of yne amines to form an endo-adduct intermediate, which reacts with electron-deficient azides to produce cyclic amidines <06JA12366>. Selected examples of an interesting synthetic route to tropene derivatives 165 via a dual hydroamination strategy is shown below. This one-step reaction makes use of a palladium catalyst and takes place by sequential intermolecular hydroamination of cycloheptatriene with aryl, heteroaryl, and primary alkyl amines to generate intermediate 166, followed by transannular intramolecular hydroamination <06JA8134>. 

Intramolecular palladium-catalyzed aryl amination chemistry is used to synthesize benzimidazoles. When NaOH in toluene is used as a base, the reaction rate is very slow. But aqueous reaction conditions (20% water/xylene) led to complete conversion of an amidine to benzimidazole 3 after two hours at reflux [7]. 

Intramolecular N-arylations of amidines 83 led to benzimidazoles 84 mediated by potassium hydroxide (140L536). Multi-substituted benzimidazoles 86 were obtained from amidines 85 via iodine(III)-promoted oxidative C(sp )-C(sp ) and C(sp )-N bond formation (140L2822). Direct... 

Carboxylic acid anhydrides. A soln. of triflic anhydride in ethylene dichloride added dropwise to a soln. of Ph3PO in the same solvent at 0° under N2 after 15 min a soln. of / -toluic acid in ethylene dichloride added followed by EtjN, and stirred for 15 min - p-toluic anhydride. Y 93%. Redox side reactions are avoided, and ketones, esters and ethers unaffected. F.e. inch ketenes, carboxylic acid esters (incl. aryl esters) and amides, amidines from carboxylic acid amides, benzimidazoles, and intramolecular ar. acylation, also using N-diphenylphosphinyl-N -methylpiperazine (without the need for an additional base), s. J.B. Hendrickson, M.S. Hussoin, J. Org. Chem. 54, 1144-9 (1989) alternative prepn. of reagents cf. D. Crich, H. Dyker, Tetrahedron Letters 30, 475-6 (1989). 

An analogous reaction sequence can be used to generate benzimidazoles and aminobenzimidazoles, involving the palladium-catalyzed intramolecular cyclization of aryl bromide-substituted amidines and guanidines, respectively (e.g.. Scheme 6.37) [48]. With aryl bromides, simple Pd(PPh3)4 or Pd2dba3/PPh3 catalysts are sufficient to mediate cyclization. This same approach is equally applicable to indazoles and polycyclic benzimidazoles [49]. 

Despite this limitation, Esser and coworkers have managed to demonstrate the applicability of this 1,3-aryl migration, under neutral or basic conditions, in a synthesis of 2-arylamino-4,5,6,7-tetrahydro-l//-l,3-diazepines (51) (Scheme 18.10) [31], Mechanistic studies on this amidine rearrangement in which a 1 1 mixture of two different rearrangement precursors (i.e., 50) was reacted showed no evidence of intermolecular aryl transfer, thus providing evidence for an intramolecular transformation that, in comparison to the Chapman rearrangement, should proceed via a spirocyclic intermediate such as 52. 

Li S, li Z, Yuan Y, Peng D, Li Y, Zhang L, Wu Y (2012) Au(l)-catalyzed intramolecular hydroamination of the fluorinated iV -aryl-AJ-propaigyl amidines mild conditions for the synthesis of 2-fluoroalkyl imidazole derivatives. Oig Lett 14 1130-1133... 

The ease of adduct formation depends largely on the electron density on the N atom of the imine and the electrophilicity of the center carbon atom of the isocyanate. Most reactive are persubstituted guanidines and amidines on one side and aryl isocyanates with electron withdrawing substituents on the other side. The initial attack occurs on the more nucleophilic center. Delocalization of the developing charges favors intermolecular [2-I-2-I-2] cycloaddition over intramolecular [2-1-2] cycloaddition or the exchange reaction. When a hydrogen shift can occur, the intramolecular isocyanate induced enurea reaction is faster than the intermolecular [2-I-2-I-2] cycloaddition reaction. Thermodynamically controlled equilibria are established above 100 °C and the thermodynamically more stable reaction product is isolated. 

CuO (5 mol%) has been utilized for the S5mthesis of benzimidazoles in water via intramolecular N-arylation [77] (Scheme 53). Using N,N -dimethylethylendiamine (10mol %) as the ligand and K2CO3 as the base, the protocol was used for developing a small library of benzimidazoles. In order to explain the role of copper in the intramolecular N-arylation of the amidines, the authors have proposed two alternative pathways (Scheme 53). 

Scheme 15 Pd-catalyzed intramolecular N-arylation of (2-bromophenyl)amidines...

Using amidine hydrochloride as the ammonia surrogates, the Fu group developed an efficient entry to 1//-benzimidazoles 50. In their reaction, Cu-catalyzed coupling of o-haloacetanilides with amidine hydrochlorides 58 proceeded at 60-90°C to afford arylation products 59, which underwent hydrolysis and isomerization upon further heating to provide intermediates 60. Intramolecular condensation of 60 produced benzimidazoles 50 (Scheme 21) [51]. 

A CuI/DMEDA-catalyzed intramolecular coupling of A-unprotective amidines 181 has been used for assembling 1,2,4-Benzothiadiazine 1,1-dioxides 182, another important class of heterocycles for pharmaceutical design (Scheme 63) [108]. Because the preparation of the amidines 181 could be achieved via a Cul-catalyzed three-component reaction of 1-alkynes, ammonium salts and aryl sulfonyl azides, a more efficient one-pot sequential process has been developed for the synthesis of 182 from these reagents. 

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